Hyperplasia of blood vessel walls (e.g., neointimal hyperplasia, neocellullar proliferation) is believed to be an important step in the etiology of many stenotic lesions within blood vessels. In particular, neointimal hyperplasia has been identified as the primary cause of restenosis of diseased blood vessels following percutaneous balloon angioplasty and stent implantation.
Patients who suffer from diabetes have a relatively high rate of restenosis due to excessive neointimal proliferation. Additionally, in many diabetic patients, atherosclerotic disease is diffuse with ling lesions involving multiple vessels.
Currently, the treatments available to prevent restenosis following stent implantation involve either the delivery of ionizing radiation to the blood vessel wall (i.e., brachytherapy) or the delivery of antiproliferative drug such as Rapamicyn (Sirolimus) or Paclitaxel (Taxol).
Brachytherapy has been proven effective in reducing the rate of in-stent restenosis, but its use has been limited to date. Brachytherapy has been associated with untoward effects in some patients, such as subacute thrombogenicity of the irradiated blood vessel and renarrowing of the blood vessel at the edge of the stent (i.e., the “candy wrapper effect”).
Antiproliferative drugs, such as rapamycin and paclitaxel, have been used systemically for purposes other than inhibition of neoproliferation of blood vessels. For example, Rapamycin (Sirolimus) inhibits T-lymphocyte activation and proliferation downstream of IL-2 and has been administered orally to deter organ transplant rejection. Paclitaxel (Taxol) inhibits mitosis and has been administered intravenously to treat a variety of cancers. When used to deter proliferative changes in blood vessels, rapamycin (Sirolimus) and paclitaxel (Taxol) are administered directly to the affected blood vessel wall by implantation of a drug eluting stent (e.g., the Cypher™ rapamycin-eluting stent manufactured by Cordis Corporation, a Division of Johnson & Johnson, Miami Lakes, Fla. and the Taxus™ paclitaxel-eluting stent manufactured by the Scimed division of Boston Scientific, Maple Grove, Minn.
Although the currently available drug eluting stents have been shown to significantly inhibit in-stent restenosis by preventing neoproliferative changes in blood vessel walls following angioplasty and stent placement, there remains a need in the art for the development of new and different agents which may be delivered locally (e.g., by a drug eluting stent or other implant or by injection into or near a blood vessel wall) or systemically (e.g., orally, transdermally, transmucosally or by injection) to deter restenosis or other neoproliferative changes in blood vessel walls.